INDICATIONS AND USAGE

Limitations of Use: XYREM® (sodium oxybate) oral solution, 0.5 g/mL may only be dispensed to patients enrolled in the XYREM REMS Program.Cataplexy in Narcolepsy: XYREM® is indicated for the treatment of cataplexy in narcolepsy.Excessive Daytime Sleepiness in Narcolepsy: XYREM® is indicated for the treatment of excessive daytime sleepiness (EDS) in narcolepsy.

Important Safety Information

WARNING: CENTRAL NERVOUS SYSTEM DEPRESSION and MISUSE AND ABUSE

XYREM is a Central Nervous System (CNS) depressant. In clinical trials at recommended doses, obtundation and clinically significant respiratory depression occurred in XYREM-treated patients. Almost all of the patients who received XYREM during clinical trials in narcolepsy were receiving CNS stimulants.

XYREM is the sodium salt of gamma hydroxybutyrate (GHB). Abuse of GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death.

Because of the risks of CNS depression, abuse, and misuse, XYREM is available only through a restricted distribution program called the XYREM REMS Program, using the central pharmacy that is specially certified. Prescribers and patients must enroll in the program. For further information go to www.XYREMREMS.com or call 1-866-XYREM88® (1-866-997-3688).

CONTRAINDICATIONS

XYREM is contraindicated

in combination with sedative hypnotics or alcohol and

in patients with succinic semialdehyde dehydrogenase deficiency. This is a rare disorder of inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.

WARNINGS AND PRECAUTIONS

Central Nervous System Depression

The concurrent use of XYREM with other CNS depressants, including but not limited to opioid analgesics, benzodiazepines, sedating antidepressants or antipsychotics, sedating anti-epileptic drugs, general anesthetics, muscle relaxants, and/or illicit CNS depressants, may increase the risk of respiratory depression, hypotension, profound sedation, syncope, and death. If use of these CNS depressants in combination with XYREM is required, dose reduction or discontinuation of one or more CNS depressants (including XYREM) should be considered. In addition, if short-term use of an opioid (eg, post- or perioperative) is required, interruption of treatment with XYREM should be considered.

After first initiating treatment and until certain that XYREM does not affect them adversely (eg, impair judgment, thinking, or motor skills), caution patients against hazardous activities requiring complete mental alertness or motor coordination such as operating hazardous machinery, including automobiles or airplanes. Also caution patients against these hazardous activities for at least 6 hours after taking the second nightly dose. Patients should be queried about CNS depression-related events upon initiation of XYREM therapy and periodically thereafter.

Abuse and Misuse

XYREM is a Schedule III controlled substance. The active ingredient of XYREM, sodium oxybate or gamma hydroxybutyrate (GHB), is a Schedule I controlled substance. Abuse of illicit GHB, either alone or in combination with other CNS depressants, is associated with CNS adverse reactions, including seizure, respiratory depression, decreases in the level of consciousness, coma, and death. The rapid onset of sedation, coupled with the amnestic features of XYREM, particularly when combined with alcohol, has proven to be dangerous for the voluntary and involuntary user (eg, assault victim). Physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely.

XYREM REMS Program

Because of the risks of central nervous system depression and abuse/misuse, XYREM is available only through a restricted distribution program called the XYREM REMS Program.

Required components of the XYREM REMS Program include:

Healthcare Providers who prescribe XYREM are specially certified

XYREM will be dispensed only by the central pharmacy that is specially certified

XYREM will be dispensed and shipped only to patients who are enrolled in the XYREM REMS Program with documentation of safe use

Respiratory Depression and Sleep-Disordered Breathing

XYREM may impair respiratory drive, especially in patients with compromised respiratory function. In overdoses, life-threatening respiratory depression has been reported. Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients and in postmenopausal women not on hormone replacement therapy as well as among patients with narcolepsy.

Depression and Suicidality

In clinical trials in patients with narcolepsy (n=781), there were two suicides and two attempted suicides in
XYREM-treated patients, including three patients with a previous history of depressive psychiatric disorder. Of the two suicides, one patient used XYREM in conjunction with other drugs. XYREM was not involved in the second suicide. Adverse reactions of depression were reported by 7% of 781 XYREM-treated patients, with four patients (<1%) discontinuing because of depression. In most cases, no change in XYREM treatment was required. The emergence of depression in patients treated with XYREM requires careful and immediate evaluation. Patients with a previous history of a depressive illness and/or suicide attempt should be monitored carefully for the emergence of depressive symptoms while taking XYREM.

Other Behavioral or Psychiatric Adverse Reactions

During clinical trials in narcolepsy, 3% of 781 patients treated with XYREM experienced confusion, with incidence generally increasing with dose. In a controlled trial where patients were randomized to fixed total daily doses of 3 g, 6 g, or 9 g per night or placebo, a dose-response relationship for confusion was demonstrated, with 17% of patients at 9 g per night experiencing confusion. Patients treated with XYREM who become confused should be evaluated fully, and appropriate intervention considered on an individual basis.

Anxiety occurred in 5.8% of the 874 patients receiving XYREM in clinical trials in another population. The emergence of or increase in anxiety in patients taking XYREM should be carefully monitored. Other neuropsychiatric reactions reported in XYREM clinical trials and the post-marketing setting included hallucinations, paranoia, psychosis, aggression, and agitation. The emergence of thought disorders and/or behavior abnormalities requires careful and immediate evaluation.

Parasomnias

Instances of significant injury or potential injury were associated with sleepwalking during a clinical trial of XYREM in patients with narcolepsy. Episodes of sleepwalking should be fully evaluated and appropriate interventions considered.

Use in Patients Sensitive to High Sodium Intake

XYREM has a high salt content. In patients sensitive to salt intake (eg, those with heart failure, hypertension, or renal impairment), consider the amount of daily sodium intake in each dose of XYREM.

MOST COMMON ADVERSE REACTIONS

In three controlled clinical trials, the most common adverse reactions (incidence ≥5% and twice the rate seen with placebo) in XYREM-treated patients were nausea (20%), dizziness (15%), vomiting (11%), somnolence (8%), enuresis (7%), and tremor (5%).

ADDITIONAL ADVERSE REACTIONS

Additional adverse reactions that occurred in ≥2% of patients in any treatment group for three controlled trials and were more frequent in any XYREM treatment group than with placebo were diarrhea, upper abdominal pain, dry mouth, pain, feeling drunk, peripheral edema, extremity pain, cataplexy, muscle spasms, paresthesia, attention disturbance, sleep paralysis, disorientation, anxiety, irritability, sleepwalking, and hyperhidrosis.

Discontinuation: Of the 398 XYREM-treated patients with narcolepsy, 10.3% of patients discontinued because of adverse reactions compared with 2.8% of patients receiving placebo. The most common adverse reaction leading to discontinuation was nausea (2.8%). The majority of adverse reactions leading to discontinuation began during the first few weeks of treatment.

Dose-Response Information: In clinical trials in narcolepsy, a dose-response relationship was observed for nausea, vomiting, paresthesia, disorientation, irritability, disturbance in attention, feeling drunk, sleepwalking, and enuresis. The incidence of all these reactions was notably higher at 9 g per night. In controlled trials in narcolepsy, discontinuations of treatment due to adverse reactions were greater at higher doses of XYREM.

DRUG INTERACTIONS

XYREM should not be used in combination with alcohol or sedative hypnotics. Use of other CNS depressants may potentiate the CNS-depressant effects of XYREM.

Concomitant use of XYREM with divalproex sodium resulted in a 25% mean increase in systemic exposure to XYREM (AUC ratio range of 0.8 to 1.7) and in a greater impairment on some tests of attention and working memory. An initial XYREM dose reduction of at least 20% is recommended if divalproex sodium is prescribed to patients already taking XYREM. Prescribers are advised to monitor patient response closely and adjust dose accordingly if concomitant use of XYREM and divalproex sodium is warranted.

PREGNANCY AND LACTATION

There are no adequate data on the developmental risk associated with the use of sodium oxybate in pregnant women. XYREM should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

PEDIATRIC USE

Safety and effectiveness in pediatric patients have not been established.

GERIATRIC USE

Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HEPATIC IMPAIRMENT

The starting dose of XYREM should be reduced by one-half in patients with liver impairment.

Dose Modification in Patients with Hepatic Impairment: The recommended starting dose in patients with hepatic impairment is 2.25 g per night administered orally in two equal, divided doses: approximately 1.13 g at bedtime and approximately 1.13 g taken 2.5 to 4 hours later.

DEPENDENCE AND TOLERANCE

There have been case reports of withdrawal, ranging from mild to severe, following discontinuation of illicit use of GHB at frequent repeated doses (18 g to 250 g per day) in excess of the therapeutic dose range. Signs and symptoms of GHB withdrawal following abrupt discontinuation included insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, tachycardia, headache, dizziness, rebound fatigue and sleepiness, confusion, and, particularly in the case of severe withdrawal, visual hallucinations, agitation, and delirium. These symptoms generally abated in 3 to 14 days. In cases of severe withdrawal, hospitalization may be required. The discontinuation effects of XYREM have not been systematically evaluated in controlled clinical trials.

In the clinical trial experience with XYREM in narcolepsy/cataplexy patients at therapeutic doses, two patients reported anxiety and one reported insomnia following abrupt discontinuation at the termination of the clinical trial; in the two patients with anxiety, the frequency of cataplexy had increased markedly at the same time. Tolerance to XYREM has not been systematically studied in controlled clinical trials. There have been some case reports of symptoms of tolerance developing after illicit use at dosages far in excess of the recommended XYREM regimen.

XYREM is a Schedule III controlled substance and is the sodium salt of gamma hydroxybutyrate (GHB), a Schedule I controlled substance. Abuse or misuse of illicit GHB is associated with CNS adverse reactions, including seizure, respiratory depression, decreased consciousness, coma, and death.

Because of the risks of CNS depression, abuse, and misuse, XYREM is available only through a restricted distribution program called the XYREM REMS Program, using the central pharmacy that is specially certified. Prescribers and patients must enroll in the program.